Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000809907 | SCV000950089 | pathogenic | Charcot-Marie-Tooth disease axonal type 2F | 2023-09-25 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 182 of the HSPB1 protein (p.Pro182Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary motor neuropathy (PMID: 16155736). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 7483). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HSPB1 protein function. Experimental studies have shown that this missense change affects HSPB1 function (PMID: 25220807). This variant disrupts the p.Pro182 amino acid residue in HSPB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18325928, 27816334, 29381233). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Molecular Genetics, |
RCV000007911 | SCV002503626 | likely pathogenic | Neuronopathy, distal hereditary motor, type 2B | 2022-04-22 | criteria provided, single submitter | clinical testing | This sequence change is predicted to replace proline with serine at codon 182 of the HSPB1 protein (p.(Pro182Ser)). The proline residue is highly conserved (100 vertebrates, UCSC), and is located in the in the IPI/V motif in the C-terminal domain. It is a critical residue for cis-trans proline isomerisation in regulating the oligomerisation of small heat shock proteins (PMID: 28547731). There is a moderate physicochemical difference between proline and serine. The variant is absent in a large population cohort (gnomAD v2.1 and v3.1). It has been identified in at least three individuals with distal hereditary motor neuropathy, and one of these was confirmed de novo (PMID: 16155736, Invitae, Royal Melbourne Hospital). In functional analyses the variant induces HspB1 aggregation and decreases chaperone activity (PMID: 25220807). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Additionally, two different missense changes at the same position (Pro182Leu, Pro182Ala) have been seen in individuals with hereditary neuropathies (ClinVar). Based on the classification scheme RMH Modified ACMG Guidelines v1.3.1, this variant is classified as LIKELY PATHOGENIC . Following criteria are met: PS2_Moderate, PM1, PM2_Supporting, PS3_Supporting, PS4_Supporting, PP3. |
| Victorian Clinical Genetics Services, |
RCV000809907 | SCV002557591 | pathogenic | Charcot-Marie-Tooth disease axonal type 2F | 2022-02-02 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as a Pathogenic. Following criteria are met: 0104 - Dominant negative is a known mechanism of disease in this gene and is associated with axonal Charcot-Marie-Tooth disease type 2F (MIM#606595) and distal hereditary motor neuronopathy type IIB (MIM#608634) (PMID: 25220807). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to serine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated sHSP domain (Uniprot). (I) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Two alternative changes to an alanine or a leucine have been reported in multiple individuals with Charcot-Marie-Tooth disease or distal hereditary motor neuronopathy (ClinVar, PMID: 15122254, 27816334, 29381233). An additional change to a threonine has also been reported once as VUS in ClinVar. (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported in individuals with Charcot-Marie-Tooth disease or distal hereditary motor neuronopathy, including one de novo occurrence (ClinVar, PMID: 16155736). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional analysis shows that this variant interacts and sequestrates the WT protein and inhibiting its normal function (PMID: 25220807). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |
| OMIM | RCV000007911 | SCV000028116 | pathogenic | Neuronopathy, distal hereditary motor, type 2B | 2005-01-01 | no assertion criteria provided | literature only |